eMedicine Specialties > Pediatrics: Cardiac Disease and Critical Care Medicine > Neonatology

Hypoxic-Ischemic Encephalopathy: Differential Diagnoses & Workup

Author: Santina A Zanelli, MD, Assistant Professor, Department of Pediatrics, Division of Neonatology, University of Virginia Health System
Coauthor(s): Dirk P Stanley, MD, Resident Physician, Department of Pathology, University of Virginia Health System; David A Kaufman, MD, Associate Professor of Pediatrics, Neonatal Clinical Trials Group Director, ECMO Director, Department of Pediatrics, Division of Neonatology, University of Virginia Health System
Contributor Information and Disclosures

Updated: Nov 19, 2009

Differential Diagnoses

Methylmalonic Acidemia
Propionic Acidemia (Propionyl CoA Carboxylase Deficiency)

Other Problems to Be Considered

Several inborn errors of metabolism can present in the neonatal period with features of hypoxic-ischemic encephalopathy (HIE).28 Those include the following:

  • Nonketotic hyperglycinemia
  • Disorders of pyruvate metabolism
  • Urea cycle defects
  • Zellweger syndrome
  • Mitochondrial disorders

Other diagnosis should also be included in the differential diagnosis, including the following:

  • Neuromuscular disorders including neonatal myopathies
  • Brain tumors
  • Developmental defects
  • Infections

Workup

Laboratory Studies

There are nor specific tests to confirm or exclude a diagnosis of hypoxic-ischemic encephalopathy (HIE) because the diagnosis is made based on the history, physical and neurological examinations, and laboratory evidence. Many of the tests are performed to assess the severity of brain injury and to monitor the functional status of systemic organs. As always, the results of the tests should be interpreted in conjunction with the clinical history and the findings from physical examination.

Laboratory studies should include the following:

  • Serum electrolyte levels
    • In severe cases, daily assessment of serum electrolytes are valuable until the infant's status improves. Markedly low serum sodium, potassium, and chloride levels in the presence of reduced urine flow and excessive weight gain may indicate acute tubular damage or syndrome of inappropriate antidiuretic hormone (SIADH) secretion, particularly during the initial 2-3 days of life.
    • Similar changes may be seen during recovery; increased urine flow may indicate ongoing tubular damage and excessive sodium loss relative to water loss
  • Renal function studies: Serum creatinine levels, creatinine clearance, and BUN levels suffice in most cases.
  • Cardiac and liver enzymes: These values are an adjunct to assess the degree of hypoxic-ischemic injury to these other organs. These findings may also provide some insight into injuries to other organs, such as the bowel.
  • Coagulation system evaluation: This includes prothrombin time, partial thromboplastin time, and fibrinogen levels.
  • ABG: Blood gas monitoring is used to assess acid-base status and to avoid hyperoxia and hypoxia as well as hypercapnia and hypocapnia.

Imaging Studies

  • Brain MRI
    • MRI is the imaging modality of choice for the diagnosis and follow-up of infants with moderate-to-severe hypoxic-ischemic encephalopathy (HIE).29,30,31 Conventional MRI sequences (T1w and T2w) provide information on the status of myelination and preexisting developmental defects of the brain. When performed after the first day (and particularly after day 4), conventional images may accurately demonstrate the injury pattern as area of hyperintensity. Conventional images are most helpful at age 7-10 days, when the diffusion-weighted imaging (DWI) findings have pseudonormalized.
      • Following a severe asphyxial event, a central pattern of injury is seen with injury to (1) the deep gray matter (ie, putamina, ventrolateral thalamus, hippocampi, dorsal brainstem, or lateral geniculate nucleus) and (2) the perirolandic cortex. These areas contain the highest concentration of N-methyl-D-aspartate (NMDA) receptors and are actively myelinating.
      • Less severe or partial insult results in injury to the intervascular boundaries areas and is also called watershed injury. This type of lesions manifests in the infants as proximal extremity weakness or spasticity.
      • Decreased signal in the posterior limb of the internal capsule (PLIC) on T1w images may be noted. The absence of normal signal (high intensity on T1w images) in the PLIC of infants older than 38 weeks' gestation is a strong predictor of abnormal motor outcomes in these infants.32
    • DWI allows earlier identification of injury patterns in the first 24-48 hours. The MRI sequence identifies areas of edema and, hence, injured areas. DWI changes peak at 3-5 day and pseudonormalizes by the end of the first week. In neonates, DWI changes may underestimate the extent of injury, most likely because of the importance of apoptosis in the ultimate extent of neurological injury.29
    • MRI is also a useful tool in the determination of prognosis. Studies indicate that infants with predominant injuries to the basal ganglia or thalamus have an unfavorable neurological outcome when compared with infants with a white matter predominant pattern of injury. Abnormal signals in the PLIC have also been associated with poor neurological outcome.
    • MRI is also useful for follow-up. In any newly diagnosed case of cerebral palsy, MRI should be considered because it may help in establishing the cause. Note that the interpretation of MRI in infants requires considerable expertise.
    • Magnetic resonance spectroscopy (MRS) allows for quantification of intracellular molecules. Proton MRS allows identification of cerebral lactate, which persist for weeks following a significant hypoxic-ischemic injury. Phosphorous MRS allows for real-time quantification of ATP, phosphorus creatinine, inorganic phosphorous, and intracellular pH levels.
  • Cranial ultrasonography: Although portable and convenient, cranial ultrasonography has a low sensitivity (50%) for the detection of anomalies associated with hypoxic-ischemic encephalopathy. Findings include global increase in cerebral echogenicity and obliteration of cerebrospinal fluid (CSF) containing spaces suggestive of cerebral edema. Increase in the echogenicity of deep gray matter structures may also be identified, typically when ultrasonography is performed after 7 days of life. Finally, head ultrasonography is helpful upon admission, particularly in patients evaluated for hypothermia therapy, to rule out intracerebral or intraventricular hemorrhages.
  • Head CT scanning
    • A CT scan of the head can be useful to confirm cerebral edema (obliteration of cerebral ventricles, blurring of sulci), manifested as narrowness of the lateral ventricles and flattening of gyri. Areas of reduced density that indicate evolving zones of infarction may be present.
    • Evidence of hemorrhage in the ventricles or in the cerebral parenchyma may also be seen. Although intraventricular hemorrhages are rare in term infants, cerebral artery occlusions and infarctions can be detected with Doppler flow studies and confirmed with radiographic imaging using radio-opaque contrast materials.
    • In cases of suspected posterior cranial fossa hemorrhage, a CT scan may be diagnostic. An early diagnosis may help in obtaining early neurosurgical consultation and, possibly, surgical therapy.
    • However, evidence suggests that even a single CT scan exposes children to potentially harmful radiation.33 In view of this evidence, MRI has now largely supplanted head CT in the evaluation of neonates with hypoxic-ischemic encephalopathy.
  • Echocardiography: In infants requiring inotropic support, echocardiography (ECHO) helps to define myocardial contractility and the existence of structural heart defects, if any.

Other Tests

  • Amplitude-integrated electroencephalography (aEEG)
    • Several studies have shown that a single-channel aEEG performed within a few hours of birth can help evaluate the severity of brain injury in the infant with hypoxic-ischemic encephalopathy.34,35,36 The abnormalities seen in infants with moderate-to-severe hypoxic-ischemic encephalopathy include the following:
      • Discontinuous tracing characterized by a lower margin below 5 mV and an upper margin above 10 mV
      • Burst suppression pattern characterized by a background with minimum amplitude (0-2 mV) without variability and occasional high voltage bursts (>25 mV)
      • Continuous low voltage pattern characterized by a continuous low voltage background (<5 mV)
      • Inactive pattern with no detectable cortical activity
      • Seizures, usually seen as an abrupt rise in both the lower and upper margins
    • In addition, aEEG findings have been used as criteria for inclusion in the CoolCap trial of selective head cooling.18,37,25 However, some evidence argues against the use of aEEG as a tool to exclude infants with hypoxic-ischemic encephalopathy from receiving hypothermia therapy.
    • Although normal aEEG findings may not necessarily mean that the brain is healthy, a severe or moderately severe aEEG abnormality may indicate brain injury and poor outcome. However, a rapid recovery (within 24 h) of abnormal aEEG findings is associated with favorable outcome in 60% of cases. Finally, in a meta-analysis of 8 studies, Spitzmiller et al concluded that aEEG can accurately predict poor outcome with a sensitivity of 91% (95% CI, 87-95) and a negative likelihood ratio of 0.09 (95% CI, 0.06-0.15).38
    • Note that considerable training is required for conducting and properly interpreting the aEEG findings.
  • Standard EEG
    • Traditional, multichannel EEG is an integral part of the evaluation of infants diagnosed with hypoxic-ischemic encephalopathy. It is a valuable tool to assess the severity of the injury and evaluate for subclinical seizures.39,40 This is particularly important for infants on assisted ventilation requiring sedation or paralysis.
    • Generalized depression of the background rhythm and voltage, with varying degrees of superimposed seizures, are early findings. EEG characteristics associated with abnormal outcomes include (1) background amplitude of less than 30 mV, (2) interburst interval of more than 30 seconds, (3) electrographic seizures, and (4) absence of sleep-wake cycle at 48 hours.
    • Caution in interpreting early severe background abnormalities needs to be applied because reverting to normal background pattern in few days of life can be associated with normal outcomes. Note that large doses of anticonvulsant therapy may alter the EEG findings.
    • Serial EEGs should be obtained to assess seizure control and evolution of background abnormalities. Early EEGs are important not only to evaluate the degree of encephalopathy and the presence of seizures but may also help establish early prognosis.41 Serial EEGs are also helpful in establishing prognosis. Improvement in the EEG findings over the first week, in conjunction with improvement in the clinical condition, may help predict a better long-term outcome.42
  • Special sensory evaluation: Screening for hearing is now mandatory in many states in the United States; in infants with hypoxic-ischemic encephalopathy, a full-scale hearing test is preferable because of an increased incidence of deafness among infants with hypoxic-ischemic encephalopathy that require assisted ventilation.
  • Retinal and ophthalmic examination: This examination may be valuable, particularly as part of an evaluation for developmental abnormalities of the brain.

Histologic Findings

  • The impressive array of neuropathologic findings that can result from a hypoxic-ischemic event can be primarily explained by the gestational time frame in which the event occurs. Prior to 20 weeks' gestation, fetal macrophages are capable of removing necrotic debris via phagocytosis, resulting in a smooth cavity without a gliotic response. Examples of lesions that can result from hypoxic-ischemic events in the second trimester include hydranencephaly, porencephaly, and schizencephaly.
  • After 20 weeks' gestation, hypoxic-ischemic insults result in astrocyte activation with subsequent gliosis. Subependymal germinal matrix hemorrhage is most common in premature infants, with hemorrhage involving the germinal matrix, lateral ventricles, and/or the adjacent parenchyma. In the full-term infant, hypoxic-ischemic events primarily result in lesions of the cerebral cortex, basal ganglia, thalamus, brain stem, or cerebellum. The location and severity of the lesions correlate with clinical symptoms, such as disturbances of consciousness, seizures, hypotonia, oculomotor-vestibular abnormalities, and feeding difficulties. The major neuropathological patterns of injury in hypoxic-ischemic encephalopathy are listed below. More than one pattern can be present.
    • Selective neuronal necrosis is the most common pattern of injury observed in hypoxic-ischemic encephalopathy and is characterized by neuronal necrosis selective to areas with higher energy demands. The following 5 major patterns have been described:
    • Diffuse: Sites of predilection for diffuse neuronal necrosis include the cerebral cortex (particularly the hippocampus), deep nuclear structures (thalamus, basal ganglia), brain stem, cerebellum, and anterior horn of the spinal cord.
    • Cerebral cortex (deep nuclear): A predominant cerebral cortex (deep nuclear) pattern of injury is present in 35-85% of infants with hypoxic-ischemic encephalopathy.
    • Brain stem (deep nuclear): Brain stem (deep nuclear) is the predominant lesion in 15-20% of infants with hypoxic-ischemic encephalopathy. Some of these lesions can evolve to status marmoratus . The 3 major features of status marmoratus include neuronal loss, gliosis and hypermyelination. This hypermyelination is believed to be secondary to myelin sheath formation and deposition around the prominent processes of reactive astrocytes. Patchy, white discoloration of the gray matter ("marbling") is sometimes observed on gross examination. This marbling is the macroscopic correlate of the hypermyelination and glial scarring seen on histologic examination. It is not seen in its complete form until the end of the first year of life.
    • Pontosubicular: This is the least common pattern and can occur in infants aged 1-2 months or younger.
    • Cerebellar: This primarily occurs in premature infants.
  • An example of severe acute hypoxic-ischemic neuronal change with associated gliosis is shown in Media files 4-5.

  • Severe acute hypoxic-ischemic neuronal change in ...

    Severe acute hypoxic-ischemic neuronal change in the basal ganglia is noted. Histologic examination reveals severe hypoxic-ischemic neuronal change, characterized by the presence of pyknotic and hyperchromatic nuclei, the loss of cytoplasmic Nissl substance, and neuronal shrinkage and angulation (arrow). These alterations begin to appear approximately 6 hours following hypoxic-ischemic insult. Reactive astrocytosis is evident approximately 24-48 hours after the primary hypoxic-ischemic event.

    [ CLOSE WINDOW ]
    Severe acute hypoxic-ischemic neuronal change in ...

    Severe acute hypoxic-ischemic neuronal change in the basal ganglia is noted. Histologic examination reveals severe hypoxic-ischemic neuronal change, characterized by the presence of pyknotic and hyperchromatic nuclei, the loss of cytoplasmic Nissl substance, and neuronal shrinkage and angulation (arrow). These alterations begin to appear approximately 6 hours following hypoxic-ischemic insult. Reactive astrocytosis is evident approximately 24-48 hours after the primary hypoxic-ischemic event.


  • Significant astrocytosis in the basal ganglia fol...

    Significant astrocytosis in the basal ganglia following hypoxic-ischemic insult is observed. An immunohistochemical stain for glial fibrillary acidic protein (GFAP) was performed on the same tissue shown in Media file 4 to demonstrate the prominent gliosis secondary to the hypoxic-ischemic event. GFAP is a useful marker to study astrocytic response to injury. This gliosis of the basal ganglia, along with subsequent hypermyelination, is responsible for the evolution of status marmoratus over months to years.

    [ CLOSE WINDOW ]
    Significant astrocytosis in the basal ganglia fol...

    Significant astrocytosis in the basal ganglia following hypoxic-ischemic insult is observed. An immunohistochemical stain for glial fibrillary acidic protein (GFAP) was performed on the same tissue shown in Media file 4 to demonstrate the prominent gliosis secondary to the hypoxic-ischemic event. GFAP is a useful marker to study astrocytic response to injury. This gliosis of the basal ganglia, along with subsequent hypermyelination, is responsible for the evolution of status marmoratus over months to years.

  • Parasagittal cerebral injury is typically bilateral and involves the parasagittal areas of the cerebral cortex (see Media file 6). The regions of the cortex most susceptible to this type of injury are the end-artery zones between the anterior, middle, and posterior cerebral arteries. These so-called watershed regions are particularly vulnerable to global hypoperfusion events; the parieto-occipital cortex is most susceptible. Parasagittal cerebral injury is most commonly seen in the full-term infant. Although most of these lesions are ischemic, approximately 25% are associated with hemorrhagic events in the perinatal period.

  • Bilateral acute infarctions of the frontal lobe a...

    Bilateral acute infarctions of the frontal lobe are shown. The infarctions depicted in the figure (arrows) are consistent with watershed infarctions secondary to global hypoperfusion. The lesions depicted in the image are consistent with an acute ischemic event, occurring within 24 hours of death. The regions most susceptible to hypoperfusion include the end-artery zones between the anterior, middle, and posterior cerebral arteries.

    [ CLOSE WINDOW ]
    Bilateral acute infarctions of the frontal lobe a...

    Bilateral acute infarctions of the frontal lobe are shown. The infarctions depicted in the figure (arrows) are consistent with watershed infarctions secondary to global hypoperfusion. The lesions depicted in the image are consistent with an acute ischemic event, occurring within 24 hours of death. The regions most susceptible to hypoperfusion include the end-artery zones between the anterior, middle, and posterior cerebral arteries.

  • Focal and multifocal ischemic brain necrosis lesions vary in terms of distribution and can be limited to a region supplied by an occluded artery or can be diffuse in cases of global hypoperfusion. Ulegyria may result, with preserved gyral crests adjacent to sulci marked by dyslamination, neuronal loss, and disorganized white myelinated fibers (see Media files 7-8).

  • A prior hypoxic-ischemic event involving the occi...

    A prior hypoxic-ischemic event involving the occipital lobe has resulted in a chronic lesion marked by dyslamination, neuronal loss, and disorganized arrangements of myelinated white matter fibers. Grossly, the lesion was marked by preserved gyral crests and involved sulci, resulting in prominent, mushroom-shaped gyri.

    [ CLOSE WINDOW ]
    A prior hypoxic-ischemic event involving the occi...

    A prior hypoxic-ischemic event involving the occipital lobe has resulted in a chronic lesion marked by dyslamination, neuronal loss, and disorganized arrangements of myelinated white matter fibers. Grossly, the lesion was marked by preserved gyral crests and involved sulci, resulting in prominent, mushroom-shaped gyri.


  • A Luxol-Fast Blue stain was performed on the same...

    A Luxol-Fast Blue stain was performed on the same tissue shown in Media file 7 to demonstrate the haphazard arrangement of myelinated white matter fibers projecting into the gray matter of the occipital cortex.

    [ CLOSE WINDOW ]
    A Luxol-Fast Blue stain was performed on the same...

    A Luxol-Fast Blue stain was performed on the same tissue shown in Media file 7 to demonstrate the haphazard arrangement of myelinated white matter fibers projecting into the gray matter of the occipital cortex.

  • Periventricular leukomalacia (PVL), also called "white matter necrosis," is macroscopically characterized by the presence of discrete cavities or foci of parenchymal softening in the periventricular areas. In some cases, PVL can not be grossly appreciated. PVL is believed to be the result of compromised boundary zone perfusion between the ventriculofugal and ventriculopetal arteries. This area is particularly vulnerable secondary to the increased metabolic demands of white matter undergoing myelination. Microscopically, PVL manifests early as geographic coagulative necrosis. As the lesion evolves, reactive astrocytes, activated microglia, and macrophages become prominent in the lesional rim (see Media files 10-11).

  • Periventricular leukomalacia is depicted. This cy...

    Periventricular leukomalacia is depicted. This cystic lesion, present in the cingulate cortex, is consistent with periventricular leukomalacia. Note the extensive hemorrhage within the cystic space as well as the hemosiderin-laden macrophages around the lesional rim.

    [ CLOSE WINDOW ]
    Periventricular leukomalacia is depicted. This cy...

    Periventricular leukomalacia is depicted. This cystic lesion, present in the cingulate cortex, is consistent with periventricular leukomalacia. Note the extensive hemorrhage within the cystic space as well as the hemosiderin-laden macrophages around the lesional rim.


  • Periventricular leukomalacia is depicted. This fi...

    Periventricular leukomalacia is depicted. This figure depicts the lesion seen in Media file 10 at higher magnification. Extensive hemosiderin and reactive astrocytosis is present surrounding the lesion (center of field). Note the proximity of the lesion to the ependymal lining of the lateral ventricle (far right).

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    Periventricular leukomalacia is depicted. This fi...

    Periventricular leukomalacia is depicted. This figure depicts the lesion seen in Media file 10 at higher magnification. Extensive hemosiderin and reactive astrocytosis is present surrounding the lesion (center of field). Note the proximity of the lesion to the ependymal lining of the lateral ventricle (far right).

More on Hypoxic-Ischemic Encephalopathy

Overview: Hypoxic-Ischemic Encephalopathy
Differential Diagnoses & Workup: Hypoxic-Ischemic Encephalopathy
Treatment & Medication: Hypoxic-Ischemic Encephalopathy
Follow-up: Hypoxic-Ischemic Encephalopathy
Multimedia: Hypoxic-Ischemic Encephalopathy
References
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References

  1. [Guideline] American Academy of Pediatrics. Relation between perinatal factors and neurological outcome. In: Guidelines for Perinatal Care. 3rd ed. Elk Grove Village, Ill: American Academy of Pediatrics; 1992:221-234.

  2. [Guideline] Committee on fetus and newborn, American Academy of Pediatrics and Committee on obstetric practice, American College of Obstetrics and Gynecology. Use and abuse of the APGAR score. Pediatr. 1996;98:141-142. [Medline].

  3. Ferriero DM. Neonatal brain injury. N Engl J Med. Nov 4 2004;351(19):1985-95. [Medline].

  4. Perlman JM. Brain injury in the term infant. Semin Perinatol. Dec 2004;28(6):415-24. [Medline].

  5. Grow J, Barks JD. Pathogenesis of hypoxic-ischemic cerebral injury in the term infant: current concepts. Clin Perinatol. Dec 2002;29(4):585-602, v. [Medline].

  6. Papile LA, Rudolph AM, Heymann MA. Autoregulation of cerebral blood flow in the preterm fetal lamb. Pediatr Res. Feb 1985;19(2):159-61. [Medline].

  7. Rosenkrantz TS, Diana D, Munson J. Regulation of cerebral blood flow velocity in nonasphyxiated, very low birth weight infants with hyaline membrane disease. J Perinatol. 1988;8(4):303-8. [Medline].

  8. Pacher P, Beckman JS, Liaudet L. Nitric oxide and peroxynitrite in health and disease. Physiol Rev. Jan 2007;87(1):315-424. [Medline].

  9. Roth SC, Baudin J, Cady E, Johal K, Townsend JP, Wyatt JS. Relation of deranged neonatal cerebral oxidative metabolism with neurodevelopmental outcome and head circumference at 4 years. Dev Med Child Neurol. Nov 1997;39(11):718-25. [Medline].

  10. Berger R, Garnier Y. Pathophysiology of perinatal brain damage. Brain Res Brain Res Rev. Aug 1999;30(2):107-34. [Medline].

  11. Rivkin MJ. Hypoxic-ischemic brain injury in the term newborn. Neuropathology, clinical aspects, and neuroimaging. Clin Perinatol. Sep 1997;24(3):607-25. [Medline].

  12. Vannucci RC. Mechanisms of perinatal hypoxic-ischemic brain damage. Semin Perinatol. Oct 1993;17(5):330-7. [Medline].

  13. Vannucci RC, Yager JY, Vannucci SJ. Cerebral glucose and energy utilization during the evolution of hypoxic-ischemic brain damage in the immature rat. J Cereb Blood Flow Metab. Mar 1994;14(2):279-88. [Medline].

  14. de Haan HH, Hasaart TH. Neuronal death after perinatal asphyxia. Eur J Obstet Gynecol Reprod Biol. Aug 1995;61(2):123-7. [Medline].

  15. McLean C, Ferriero D. Mechanisms of hypoxic-ischemic injury in the term infant. Semin Perinatol. Dec 2004;28(6):425-32. [Medline].

  16. Bryce J, Boschi-Pinto C, Shibuya K, Black RE. WHO estimates of the causes of death in children. Lancet. Mar 26-Apr 1 2005;365(9465):1147-52. [Medline].

  17. Lawn J, Shibuya K, Stein C. No cry at birth: global estimates of intrapartum stillbirths and intrapartum-related neonatal deaths. Bull World Health Organ. Jun 2005;83(6):409-17. [Medline].

  18. Gluckman PD, Wyatt JS, Azzopardi D, et al. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicenter randomised trial. Lancet. 2005;365:663-70. [Medline].

  19. Shankaran S, Laptook AR, Ehrenkranz RA, et al. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. Oct 13 2005;353(15):1574-84. [Medline].

  20. van Handel M, Swaab H, de Vries LS, Jongmans MJ. Long-term cognitive and behavioral consequences of neonatal encephalopathy following perinatal asphyxia: a review. Eur J Pediatr. Jul 2007;166(7):645-54. [Medline].

  21. Pin TW, Eldridge B, Galea MP. A review of developmental outcomes of term infants with post-asphyxia neonatal encephalopathy. Eur J Paediatr Neurol. May 2009;13(3):224-34. [Medline].

  22. Simon NP. Long-term neurodevelopmental outcome of asphyxiated newborns. Clin Perinatol. Sep 1999;26(3):767-78. [Medline].

  23. Martin-Ancel A, Garcia-Alix A, Gaya F, Cabanas F, Burgueros M, Quero J. Multiple organ involvement in perinatal asphyxia. J Pediatr. 1995;127:786-793. [Medline].

  24. Shah P, Riphagen S, Beyene J, Perlman M. Multiorgan dysfunction in infants with post-asphyxial hypoxic-ischaemic encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2004;89:F152-F155. [Medline].

  25. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress: A clinical and electroencphalographic study. Archives of Neur. 1976;33:696-705.

  26. Badawi N, Kurinczuk JJ, Keogh JM, et al. Antepartum risk factors for newborn encephalopathy: the Western Australian case-control study. British Medical Journal. 1998;317:1549-1553. [Medline].

  27. Graham EM, Ruis KA, Hartman AL, Northington FJ, Fox HE. A systematic review of the role of intrapartum hypoxia-ischemia in the causation of neonatal encephalopathy. Am J Obstet Gynecol. Dec 2008;199(6):587-95. [Medline].

  28. Enns, GM. Inborn errors of metabolism masquerading as hypoxic-ischemic encephalopathy. Neoreviews. 2005;6:e549-e558.

  29. Huang BY, Castillo M. Hypoxic-ischemic brain injury: imaging findings from birth to adulthood. Radiographics. Mar-Apr 2008;28(2):417-39; quiz 617. [Medline].

  30. Latchaw RE, Truwit CE. Imaging of perinatal hypoxic-ischemic brain injury. Semin Pediatr Neurol. Mar 1995;2(1):72-89. [Medline].

  31. Rutherford M, Pennock J, Schwieso J, Cowan F, Dubowitz L. Hypoxic-ischaemic encephalopathy: early and late magnetic resonance imaging findings in relation to outcome. Arch Dis Child Fetal Neonatal Ed. 1996;75:F145-F151. [Medline].

  32. Cowan FM, de Vries LS. The internal capsule in neonatal imaging. Semin Fetal Neonatal Med. Oct 2005;10(5):461-74. [Medline].

  33. Brenner, D.J. Estimating cancer risks from pediatric CT: going from the qualitative to the quantitative. Pediatr. Radiol. 1996;32:228-231. [Medline].

  34. de Vries LS, Toet MC. Amplitude integrated electroencephalography in the full-term newborn. Clin Perinatol. 2006;33:619-632. [Medline].

  35. Hellstrom-Westas L, Rosen I. Continuous brain-function monitoring: state of the art in clinical practice. Semin Fetal Neonatal Med. 2006;11:503-511. [Medline].

  36. van Rooij LGM, Toet MC, Osredkar D, van Huffelen AC, Groenendaal F, de Vries LS. Recovery of amplitude integrated electroencephalographic background patterns within 24 hours of perinatal asphyxia. Arch. Dis. Child. Fetal Neonatal Ed. 2005;90:F245-F251. [Medline].

  37. [Best Evidence] Jacobs S, Hunt R, Tarnow-Mordi W, Inder T, Davis P. Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev. 2007;4:CD003311. [Medline].

  38. Spitzmiller RE, Phillips T, Meinzen-Derr J, Hoath SB. Amplitude-integrated EEG is useful in predicting neurodevelopmental outcome in full-term infants with hypoxic-ischemic encephalopathy: a meta-analysis. Journal of Child Neurology. 2007;22:1069-1078. [Medline].

  39. Pressler RM, Boylan GB, Morton M, Binnie CD, Rennie JM. Early serial EEG in hypoxic ischaemic encephalopathy. Clinical neurophysiology. 2001;112:31-37. [Medline].

  40. Rowe JC, Holmes GL, Hafford J, et al. Prognostic value of the electroencephalogram in term and preterm infants following neonatal seizures. Electroencephalogr Clin Neurophysiol. Mar 1985;60(3):183-96. [Medline].

  41. Murray DM, Boylan GB, Ryan CA, Connolly S. Early EEG Findings in Hypoxic-Ischemic Encephalopathy Predict Outcomes at 2 Years. Pediatrics. Aug 24 2009;[Medline].

  42. Sinclair DB, Campbell M, Byrne P, Prasertsom W, Robertson CMT. EEG and long-term outcome of term infants with neonatal hypoxic-ischemic encephalopathy. Clinical neurophysiology. 1999;110:655-659. [Medline].

  43. Shankaran S. The postnatal management of the asphyxiated term infant. Clin Perinatol. Dec 2002;29(4):675-92. [Medline].

  44. Stola A, Perlman J. Post-resuscitation strategies to avoid ongoing injury following intrapartum hypoxia-ischemia. Semin Fetal Neonatal Med. Dec 2008;13(6):424-31. [Medline].

  45. Perlman JM. Intervention strategies for neonatal hypoxic-ischemic cerebral injury. Clin Ther. Sep 2006;28(9):1353-65. [Medline].

  46. [Guideline] Ten VS, Matsiukevich D. Room air or 100% oxygen for resuscitation of infants with perinatal depression. Curr Opin Pediatr. Apr 2009;21(2):188-93. [Medline].

  47. [Guideline] American Academy of Pediatrics. Committee on Fetus and Newborn. Use of inhaled nitric oxide. Pediatrics. Aug 2000;106(2 Pt 1):344-5. [Medline].

  48. [Best Evidence] Kecskes Z, Healy G, Jensen A. Fluid restriction for term infants with hypoxic-ischaemic encephalopathy following perinatal asphyxia. Cochrane Database Syst Rev. Jul 20 2005;CD004337. [Medline].

  49. Bakr AF. Prophylactic theophylline to prevent renal dysfunction in newborns exposed to perinatal asphyxia--a study in a developing country. Pediatr. Nephrol. 2005;20:1249-1252. [Medline].

  50. Bhat MA, Shah ZA, Makhdoomi MS, Mufti MH. Theophylline for renal function in term neonates with perinatal asphyxia: a randomized, placebo-controlled trial. J. Pediatr. 2006;149:180-184. [Medline].

  51. Jenik AG, Ceriani Cernadas JM, Gorenstein A, et al. A randomized, double-blind, placebo-controlled trial of the effects of prophylactic theophylline on renal function in term neonates with perinatal asphyxia. Pediatrics. 2000;105:E45. [Medline].

  52. Salhab WA, Wyckoff MH, Laptook AR, Perlman JM. Initial hypoglycemia and neonatal brain injury in term infants with severe fetal acidemia. Pediatrics. Aug 2004;114(2):361-6. [Medline].

  53. Laptook A, Tyson J, Shankaran S, et al. Elevated temperature after hypoxic-ischemic encephalopathy: risk factor for adverse outcomes. Pediatrics. Sep 2008;122(3):491-9. [Medline].

  54. Miller SP, Weiss J, Barnwell A, et al. Seizure-associated brain injury in term newborns with perinatal asphyxia. Neurology. Feb 26 2002;58(4):542-8. [Medline].

  55. Scher MS. Neonatal seizures and brain damage. Pediatr Neurol. Nov 2003;29(5):381-90. [Medline].

  56. Holmes GL. Effects of seizures on brain development: lessons from the laboratory. Pediatr Neurol. Jul 2005;33(1):1-11. [Medline].

  57. Boylan GB, Rennie JM, Chorley G, et al. Second-line anticonvulsant treatment of neonatal seizures: a video-EEG monitoring study. Neurology. Feb 10 2004;62(3):486-8. [Medline].

  58. Boylan GB, Rennie JM, Pressler RM, Wilson G, Morton M, Binnie CD. Phenobarbitone, neonatal seizures, and video-EEG. Arch Dis Child Fetal Neonatal Ed. May 2002;86(3):F165-70. [Medline].

  59. Painter MJ, Scher MS, Stein AD, Armatti S, Wang Z, Gardiner JC, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. Aug 12 1999;341(7):485-9. [Medline].

  60. Castro Conde JR, Hernandez Borges AA, et al. Midazolam in neonatal seizures with no response to phenobarbital. Neurology. Mar 8 2005;64(5):876-9. [Medline].

  61. Maytal J, Novak GP, King KC. Lorazepam in the treatment of refractory neonatal seizures. J Child Neurol. Oct 1991;6(4):319-23. [Medline].

  62. Gunn AJ, Gunn TR. The 'pharmacology' of neuronal rescue with cerebral hypothermia. Early Hum Dev. Nov 1998;53(1):19-35. [Medline].

  63. Gunn AJ. Cerebral hypothermia for prevention of brain injury following perinatal asphyxia. Curr Opin Pediatr. 2000;12(2):111-115. [Medline].

  64. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: safety outcomes. Pediatr Neurol. 2005;32 (1):18-24. [Medline].

  65. Eicher DJ, Wagner CL, Katikaneni LP, et al. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2006;34(2):169. [Medline].

  66. Shankaran S, Pappas A, Laptook AR, et al. Outcomes of safety and effectiveness in a multicenter randomized, controlled trial of whole-body hypothermia for neonatal hypoxic-ischemic encephalopathy. Pediatrics. Oct 2008;122(4):e791-8. [Medline].

  67. Laptook AR. Use of therapeutic hypothermia for term infants with hypoxic-ischemic encephalopathy. Pediatr Clin North Am. Jun 2009;56(3):601-16, Table of Contents. [Medline].

  68. Shankaran S. Neonatal encephalopathy: treatment with hypothermia. J Neurotrauma. Mar 2009;26(3):437-43. [Medline].

  69. Wilkinson DJ. Cool heads: ethical issues associated with therapeutic hypothermia for newborns. Acta Paediatr. Feb 2009;98(2):217-20. [Medline].

  70. Perlman M, Shah PS. Ethics of therapeutic hypothermia. Acta Paediatr. Feb 2009;98(2):211-3. [Medline].

  71. Edwards AD, Azzopardi DV. Therapeutic hypothermia following perinatal asphyxia. Arch Dis Child Fetal Neonatal ed. 2006;91:F127-F131. [Medline].

  72. Fairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. Journal of Perinatology. 2009;In press.

  73. Schulzke SM, Rao S, Patole SK. A systematic review of cooling for neuroprotection in neonates with hypoxic ischemic encephalopathy - are we there yet?. BMC Pediatrics. 2007;7:30. [Medline].

  74. Shah PS, Ohlsson A, Perlman M. Hypothermia to treat neonatal hypoxic ischemic encephalopathy: systematic review. Arch Pediatr Adolesc Med. 2007;161:951-958. [Medline].

  75. [Best Evidence] Azzopardi DV, Strohm B, Edwards AD, et al. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. Oct 1 2009;361(14):1349-58. [Medline].

  76. Zanelli SA, Naylor M, Dobbins N, et al. Implementation of a 'Hypothermia for HIE' program: 2-year experience in a single NICU. J Perinatol. 2008;28(3):171-175. [Medline].

  77. Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics. Dec 1997;100(6):1004-14. [Medline].

  78. Hall RT, Hall FK, Daily DK. High-dose phenobarbital therapy in term newborn infants with severe perinatal asphyxia: a randomized, prospective study with three-year follow-up. J Pediatr. Feb 1998;132(2):345-8. [Medline].

  79. Goldberg RN, Moscoso P, Bauer CR, et al. Use of barbiturate therapy in severe perinatal asphyxia: a randomized controlled trial. J Pediatr. Nov 1986;109(5):851-6. [Medline].

  80. [Best Evidence] Evans DJ, Levene MI, Tsakmakis M. Anticonvulsants for preventing mortality and morbidity in full term newborns with perinatal asphyxia. Cochrane Database Syst Rev. Jul 18 2007;CD001240. [Medline].

  81. Zhu C, Kang W, Xu F, et al. Erythropoietin improved neurologic outcomes in newborns with hypoxic-ischemic encephalopathy. Pediatrics. Aug 2009;124(2):e218-26. [Medline].

  82. Van Bel F, Shadid M, Moison RM, et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics. Feb 1998;101(2):185-93. [Medline]. [Full Text].

  83. Robertson CM, Perlman M. Follow-up of the term infant after hypoxic-ischemic encephalopathy. Paediatr Child Health. May 2006;11(5):278-82. [Medline].

  84. Depp R. Perinatal asphyxia: assessing its causal role and timing. Semin Pediatr Neurol. Mar 1995;2(1):3-36. [Medline].

  85. Patel J, Edwards AD. Prediction of outcome after perinatal asphyxia. Curr Opin Pediatr. Apr 1997;9(2):128-32. [Medline].

  86. Gunn AJ, Wyatt JS, Whitelaw A, et al. Therapeutic hypothermia changes the prognostic value of clinical evaluation of neonatal encephalopathy. J Pediatr. Jan 2008;152(1):55-8, 58.e1. [Medline].

  87. Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. 1: J Clin Invest. 1997;99(2):248-256. [Medline].

  88. Gunn AJ, Hoehn T, Hansmann G, et al. Hypothermia: an evolving treatment for neonatal hypoxic ischemic encephalopathy. Pediatrics. 2008;121:648-649. [Medline].

  89. Volpe JJ. Hypoxic-ischemic encephalopathy. In: Neurology of the newborn. 5th. Saunders - Elsevier; 2008:6-9.

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Further Reading

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Keywords

hypoxic-ischemic encephalopathy, neonatal encephalopathy, hypothermia, HIE, perinatal asphyxia, birth asphyxia, neonatal asphyxia, tricuspid regurgitation, pulmonary hypertension, renal failure, oliguria, tubular failure, necrotizing enterocolitis, hypothermia therapy

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Contributor Information and Disclosures

Author

Santina A Zanelli, MD, Assistant Professor, Department of Pediatrics, Division of Neonatology, University of Virginia Health System
Santina A Zanelli, MD is a member of the following medical societies: American Academy of Pediatrics, Society for Neuroscience, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Coauthor(s)

Dirk P Stanley, MD, Resident Physician, Department of Pathology, University of Virginia Health System
Disclosure: Nothing to disclose.

David A Kaufman, MD, Associate Professor of Pediatrics, Neonatal Clinical Trials Group Director, ECMO Director, Department of Pediatrics, Division of Neonatology, University of Virginia Health System
David A Kaufman, MD is a member of the following medical societies: American Academy of Pediatrics, European Society for Paediatric Infectious Diseases, Medical Society of Virginia, Pediatric Infectious Diseases Society, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Medical Editor

Ted Rosenkrantz, MD, Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine
Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Brian S Carter, MD, FAAP, Professor of Pediatrics (Neonatology), Vanderbilt University School of Medicine; Co-director, Pediatric Advance Comfort Team, Monroe Carell Jr Children's Hospital at Vanderbilt
Brian S Carter, MD, FAAP is a member of the following medical societies: Alpha Omega Alpha, American Academy of Hospice and Palliative Medicine, American Academy of Pediatrics, American Society for Bioethics and Humanities, American Society of Law Medicine and Ethics, National Hospice and Palliative Care Organization, and Southern Society for Pediatric Research
Disclosure: Nothing to disclose.

CME Editor

Carol L Wagner, MD, Professor of Pediatrics, Medical University of South Carolina
Carol L Wagner, MD is a member of the following medical societies: American Academy of Pediatrics, American Chemical Society, American Medical Women's Association, American Public Health Association, American Society for Bone and Mineral Research, American Society for Clinical Nutrition, Massachusetts Medical Society, National Perinatal Association, and Society for Pediatric Research
Disclosure: Nothing to disclose.

Chief Editor

Ted Rosenkrantz, MD, Professor, Departments of Pediatrics and Obstetrics/Gynecology, Division of Neonatal-Perinatal Medicine, University of Connecticut School of Medicine
Ted Rosenkrantz, MD is a member of the following medical societies: American Academy of Pediatrics, American Medical Association, American Pediatric Society, Connecticut State Medical Society, Eastern Society for Pediatric Research, and Society for Pediatric Research
Disclosure: Nothing to disclose.

 
 
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